Project summary: Substance abuse and sleep disorders are both common problems in the United States and around the world. In the US alone, over 20 million people suffer from substance abuse and/or sleep disorders. Similar to the general US population, sleep disorders and substance use are common in veterans (Newsletter of the National Office of Drug Control Policy, 2010), with populations such as those with post-traumatic stress disorder (PTSD) exhibiting especially high rates. Furthermore, sleep disorders/difficulties are often co-morbid with substance abuse (Shibley et al., 2008; Gromov and Gromov, 2009). Sleep disturbances have been demonstrated during active drug use, during withdrawal, and during abstinence periods (Morgan et al., 2006; Morgan et al., 2008). There is abundant evidence that sleep disruption in humans is a robust predictor of relapse (Brower et al., 2001) and difficulty sleeping is often cited as a reason for substance use (Brower et al., 2001). However, there have been few attempts to directly assess whether sleep loss has a causal role in future drug use. One basic, and as of yet unanswered, question is whether sleep loss augments the appetitive value a drug. In the current proposal, the hypothesis that sleep deprivation enhances the rewarding properties of cocaine will be tested using the conditioned place preference (CPP) task. The CPP task assesses cue-induced drug seeking following conditioning trials to a presumed appetitive (cocaine) and a presumed neutral (saline) stimulus. Mice will undergo short periods of sleep deprivation either prior to cocaine conditioning trials or prior to the probe trial to test whether sleep deprivation alters cocaine conditioned place preference acquisition or expression, respectively. Preliminary evidence suggests that sleep deprivation does increase preference for the cocaine-paired context. Finally, two neuromodulator systems, adenosine and orexin, will be probed as possible mechanisms by which sleep, or loss thereof, could impact reward behavior. These two systems have previously been implicated in both sleep/waking activity and addiction. Behavioral, genetic, and pharmacological techniques will be used to carry out the proposed experiments. The project mentors provide expertise in all the fields relevant to the research project, including sleep/waking behavior (Greene, Yanagisawa), addiction research (Self), and the adenosine (Greene) and orexin (Yanagisawa) systems.